Familial hypercholesterolaemia (FH) is an inherited disorder characterised by high plasma cholesterol – specifically low density lipoprotein (LDL) – and early onset cardiovascular disease. Most cases are caused by mutations in the LDL receptor gene, which is involved in removing LDL from the blood. Other causes include mutations in the apoprotein B (ApoB) gene, which affect the binding of LDL to its receptor, and in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, which reduces the number of LDL receptors.
FH is an autosomal dominant disease which results in premature cardiovascular disease, with an age of onset of around 30-40 in heterozygotes and may be fatal during childhood in homozygotes. Due to the severity of the disease, the UK Human Fertilisation and Embryology Authority (HFEA) recently granted a licence permitting pre-implantation genetic diagnosis to select against homozygous embryos (see previous news). The prevalence of heterozygotes is thought to be around 1 in 500 people, whilst homozygotes are much rarer, occurring in only 1 in a million births. Although the severity of the disease is variable, it can be devastating if left untreated, and once diagnosed, a dietary regime combined with statin therapy is very effective at lowering LDL-cholesterol, particularly in heterozygotes.
Following an extensive review and consultation, the UK National Institute for Health and Clinical Excellence (NICE) released updated guidance on the identification and management of FH on 27th August 2008. Of particular interest is the recommendation that cascade screening be systematically implemented in families affected by FH, including “the use of a nationwide, family-based, follow-up system… to enable comprehensive identification of people affected by FH”. The test will include a combination of genetic testing (where the mutation is known) and LDL concentration measurement, to identify affected first-, second- and third-degree relatives of individuals with a clinical diagnosis of FH. Given an estimated 110,000 affected individuals in the UK, and the enormous benefits of early diagnosis and treatment, the guidance also states that the possibility of FH should be considered in anyone with a raised LDL cholesterol level, especially where there is a family history of premature coronary heart disease. Since only around 10% of the total predicted number of cases have already been identified in the UK – some of whom are related – family cascade testing alone is unlikely to uncover all the remaining cases.
Comment: This strategy for population screening of FH based on cascade testing was recommended in a paper in the BMJ in 2007 (see previous news), and a similar programme has been active in the Netherlands for many years (see previous news). Though simple in concept, the necessary cascade system requires very careful design and evaluation. For example, it needs to enable coordination of testing for a whole family by different health professionals in different geographic locations, and to manage and record the different levels of consent that individuals and families have given. For this reason, the programme is unlikely to succeed unless there is an organised system of clinics in place and the relevant IT infrastructure is available. Support will be needed from specialist genetic services, particularly during developmental phases to help set up protocols and provide educational support in working with families based on sound clinical and ethical principles. The work on FH is firmly set within mainstream medicine, but will provide a valuable prototype for developments in other areas of clinical practice where there are also important genetic subsets of disease.
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